OVERALL ABSTRACT The lethal stage of metastatic prostate cancer, called castration resistant prostate cancer (CRPC), kills ~26,000 men per year in the US. Despite remarkable improvements in survival with next generation AR pathway inhibitors such as abiraterone and enzalutamide, CRPC patients ultimately progress and die from their disease. Our understanding of the mechanisms of acquired resistance to AR therapy has increased dramatically in recent years, largely based on genomic landscape analyses of tumors from CRPC patients and preclinical studies of acquired resistance in patient-derived models (organoids, PDX). Much of this progress is directly linked to the members of this Drug Resistance and Sensitivity Center (DRSC) team. A major mechanistic insight from these studies is the recognition of two categories of AR therapy resistance: one in which AR pathway signaling is restored and the other in which it remains inhibited. Underlying both categories are a heterogeneous set of resistance mechanisms, many of which were discovered by our DRSC team members. Importantly, we have shown that several of these resistance mechanisms can be targeted with current clinical grade drugs. The overarching goal of this DRSC proposal is to evaluate these translational opportunities across a unique set of preclinical organoid and PDX models (again, discovered and developed by our DRSC team members) and to catalyze the initiation of clinical studies in patients most likely to benefit based on appropriate biomarker profiles. We address this goal in three Projects. Project 1 focuses on resistance caused by restored AR pathway function, which occurs in over ~50% of CRPC patients, by targeting the glucocorticoid receptor, which is upregulated and substitutes for AR, or by further inhibition of AR signaling using drugs targeting specific components of the chromatin machinery. Project 2 will take a similar approach but will focus on the opposite category of acquired resistance (absence of restored AR pathway activity), leveraging insights from our recent data showing that cancer can revert from an AR-negative to AR-positive state by targeting specific chromatin modifiers. Project 3 integrates with Projects 1 and 2 by focusing on kinase inhibitors as an adjunct to AR pathway therapy in two distinct contexts ? PI3K/AKT activation in tumors with PTEN loss and FGFR activation in tumors with autocrine FGF8/FGF9 production. Excitingly, a recent clinical trial of combined AKT and AR inhibition, which was initiated based on our earlier work, demonstrated a significant improvement in survival for patients with PTEN loss prostate cancer. The Administrative Core will oversee the integration of the Projects with each other, with NCI scientific staff and with other DRSCs. Collectively our studies will validate various combination therapy regimens, in conjunction with molecular biomarkers for patient selection, as a critical step toward clinical translation. In addition, the drugs and targets studied here are broadly relevant for multiple cancer types.